ABSTRACT Although several therapeutic options to treat chronic diabetic wounds exist, ranging from occlusive dressings, vacuum assisted closure, skin grafts, to bioengineered skin substitutes, in many instances the wounds fail to adequately respond to treatment. Chronic wounds are characterized by a failure to progress from the pro- inflammatory to the proliferative phases of wound healing. While it has been proposed to provide exogenous growth factors to the wound to help in this transition, there has been very little success using such an approach in practice. Peptide growth factors are rapidly degraded due to the overabundance of proteases in such wounds. Furthermore, recent evidence suggests that the increased levels of advanced glycation endproducts (AGEs) in the diabetic environment may interfere with signaling pathways thus making target cells poorly responsive to bioactive peptides (such as growth factors and chemokines). We have recently shown that these responses can be restored by blocking the receptor to AGEs (RAGE) using soluble RAGE (sRAGE). We propose to develop a multi-functional nanoparticle system consisting of fusion proteins of elastin-like peptides (ELPs) with relevant bioactive peptides and sRAGE. We hypothesize that these nanoparticles can exclude proteases, protecting the attached biopeptides from degradation, and that the simultaneous release of sRAGE can restore signaling in the diabetic wound. Furthermore, these nanoparticles spontaneously and reversibly self-assemble at physiological temperatures, thus enabling rapid and inexpensive purification of the fusion proteins, and with a size below 1 micrometer, nanoparticles are small enough to be easily incorporated into topical treatment modalities, including advanced methods (e.g. skin substitutes, which typically have pore sizes in excess of 50 micrometers). To test the hypothesis, we will develop a sRAGE-ELP fusion protein and combine it with one of three different bioactive peptides that target different aspects of the wound healing process: KGF-ELP (epidermis), SDF-ELP (dermis), and ARA290-ELP (tissue protective response). Our specific aims are: (1) To develop sRAGE-ELP fusion proteins that reversibly form nanoparticles with themselves and other peptide-ELP fusion proteins. (2) To evaluate the biological activity of ELP-based nanoparticles in a simulated diabetic environment in vitro. (3) To test the effect of sRAGE-ELP nanoparticles in in vivo diabetic wound conditions.